The Duke Comprehensive Cancer Center (DCCC) is charged and empowered to serve as the center of all Duke activities in cancer and to deliver the benefits of these activities to our community and society. As a matrix center continuously supported by the National Cancer Institute (NCI) for over 31 years, the DCCC leverages Duke's basic research infrastructure with clinical oncology research excellence which is enabled by treating 4,800 new cancer patients annually, enrolling over 1,000 patients annually onto therapeutic clinical trials, and is enhanced by the presence of national oncology research resources, such as the data and statistical centers of two NCI-funded cooperative groups. These cancer research activities are supported by $48M in NCI funding (a $27M increase from 1998) and nearly $171M in total research funding (a $66M increase from 1998) and are coordinated by the DCCC and forty other center, SPORE and program project grants as well as cooperative agreements. In this competitive renewal application, we request support for 358 members (an increase of 68 since 1998) working in 11 Research Programs supported by 17 Shared Resources. Significant basic scientific advances have been made by DCCC investigators including: an understanding of DNA mismatch repair mechanisms, the role of Ras structure md signaling, and the generation of novel anti-cancer agents targeting hormone receptors. These advances are balanced with clinical and population studies such as the first clinical trial demonstrating a benefit of a new class of anti-cancer compounds, the anti-angiogenesis agents and the alpha emitter 211-Astatine; the development and demonstration of the use of umbilical cord blood as a source of stem cells for transplantation; and the development and demonstration of the use of gene expression array profiling to predict clinical outcomes in breast cancer. The DCCC has benefited from a five-year fund raising campaign which generated $113 million in philanthropic support, generated new laboratory and administrative space, enabled new Programs-in-Development in Organogenesis/Stem Cell Biology and Imaging, and enabled enhancement of Shared Resources such as Bioinformatics, Tissue and Blood Procurement, and Clinical Cellular Processing. This application for support of the DCCC articulates the principles, goals and strategies for propelling the DCCC to fully leverage the enormous advances in biomedical research to improve and extend the lives of cancer patients with cancer and at risk for cancer, and delivering these to society.